DESCRIPTION In spite of the magnitude of the problem which BPH presents, very little is known regarding the molecular mechanisms underlying the pathogenesis of this disease. It is clear from the recent progress made in the analysis of other common human diseases that linkage studies can yield tremendous insight into the specific genetic mechanisms responsible for both hereditary and sporadic forms of a given disease. The study of hereditary BPH proposed here builds upon previous work by our group demonstrating that a positive family history of BPH is a useful index of individual risk and that in some patients BPH is under direct Mendelian control. The evidence for a Mendelian form of BPH provides the basis for the linkage studies proposed here. The specific aims of this study are to: (1) Identify and recruit multiplex families, and affected sib-pairs from which DNA samples will be obtained for linkage analysis. This effort draw primarily from our access to the Merck PROSCAR database, containing over 4,000 affected men, of which over 250 are estimated to have extensive family history of BPH (3 or more first degree relatives affected). We will target the 100 most informative families from this group, based upon a hierarchical priority scheme which includes extent of family history, age of diagnosis, and volume of disease. Blood from 200 affected sibpairs will be collected for use as an independent dataset. (2) Analyze candidate genes for evidence of linkage. Candidate genes include growth factors and growth factor receptors implicated in prostatic overgrowth, as well as genes encoding steroid hormone metabolizing enzymes; (3) In the event that no evidence of linkage is obtained using a candidate gene approach, we will undertake a genome wide search for linkage. This effort will employ 350 simple sequence repeat polymorphisms spaced at 8-10cM intervals throughout the genome. The data will be analyzed for evidence of linkage using both parametric (LOD scores) and non-parametric (allele sharing methods) approaches. Both 2-point and multipoint analyses will be performed; and (4) Upon discovery of evidence of linkage, the gene location will be refined using key recombinants, and a fine structure physical map of the identified region will be constructed. Genes within the minimal region will be cloned using a cDNA hybridization selection approach. Candidate genes will be analyzed for mutations in affected individuals. The ultimate goals of this study are to confirm the existence of Mendelian forms of BPH and to identify the responsible gene(s). The identification of genes involved in an inherited form of BPH would be potentially useful for the development of novel approaches to both the prevention and treatment of this disease, and would serve as a model for the formation of the sporadic disease as well.